We want to understand functions that are distinctive to human tumor viruses in pre-neoplastic lesions and in tumor cells. These functions are potential targets for specific anti-viral therapies to treat viral associated cancers. We (Drs. Lambert and Sugden) have studied the replication of EBV and HPV for as long as their plasmid replicons have been known and recently extended our work to include KSHV. The goals of our research have been to characterize in detail the synthesis and partitioning of these viral replicons both to understand them in general and to uncover their unique features as targets for anti-viral, anti-tumor therapies. During this funding period we have developed a method to visualize individually EBV's plasmid replicons in live cells throughout a cell cycle. This approach has revealed a non-random, efficient mechanism for EBV's partitioning and an intrinsic inefficiency in its DNA synthesis. We shall extend this approach to study the synthesis and partitioning of intact genomes of EBV, KSHV, and HPV16 in their natural host cells. In particular, we shall characterize the replication of EBV during the early steps of its infection of primary B-cells to identify its mechanism of establishment, examine the efficiencies of synthesis and partitioning of KSHV as a function of the number of its terminal repeats, and determine the efficiencies and modes of the synthesis and of partitioning of HPV16 in two kinds of epithelial cells. These experiments will help to define characteristics of the synthesis and partitioning of these human tumor viruses which are likely distinct from the human genome and thus potential targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA022443-35
Application #
8377340
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
35
Fiscal Year
2012
Total Cost
$352,984
Indirect Cost
$112,831
Name
University of Wisconsin Madison
Department
Type
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Zumwalde, Nicholas A; Sharma, Akshat; Xu, Xuequn et al. (2017) Adoptively transferred V?9V?2 T cells show potent antitumor effects in a preclinical B cell lymphomagenesis model. JCI Insight 2:
Ma, Shi-Dong; Tsai, Ming-Han; Romero-Masters, James C et al. (2017) Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential. J Virol 91:
Bilger, Andrea; Plowshay, Julie; Ma, Shidong et al. (2017) Leflunomide/teriflunomide inhibit Epstein-Barr virus (EBV)- induced lymphoproliferative disease and lytic viral replication. Oncotarget 8:44266-44280
Yang, Ya-Chun; Liem, Amy; Lambert, Paul F et al. (2017) Dissecting the regulation of EBV's BART miRNAs in carcinomas. Virology 505:148-154
Iwahori, Satoko; UmaƱa, Angie C; VanDeusen, Halena R et al. (2017) Human cytomegalovirus-encoded viral cyclin-dependent kinase (v-CDK) UL97 phosphorylates and inactivates the retinoblastoma protein-related p107 and p130 proteins. J Biol Chem 292:6583-6599
Wille, Coral K; Li, Yangguang; Rui, Lixin et al. (2017) Restricted TET2 Expression in Germinal Center Type B Cells Promotes Stringent Epstein-Barr Virus Latency. J Virol 91:
Chandra, Janin; Kuo, Paula T Y; Hahn, Anne M et al. (2017) Batf3 selectively determines acquisition of CD8+ dendritic cell phenotype and function. Immunol Cell Biol 95:215-223
Pocock, Ginger M; Zimdars, Laraine L; Yuan, Ming et al. (2017) Diverse activities of viral cis-acting RNA regulatory elements revealed using multicolor, long-term, single-cell imaging. Mol Biol Cell 28:476-487
Nowak, Karolin; Linzner, Daniela; Thrasher, Adrian J et al. (2017) Absence of ?-Chain in Keratinocytes Alters Chemokine Secretion, Resulting in Reduced Immune Cell Recruitment. J Invest Dermatol 137:2120-2130
Uberoi, Aayushi; Lambert, Paul F (2017) Rodent Papillomaviruses. Viruses 9:

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